Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

central precocious puberty (CPP)

1st line – evaluation ± treatment of underlying cause

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ACUTE
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central precocious puberty (CPP)
1st line – 

evaluation ± treatment of underlying cause

In the majority of females with CPP, no apparent cause is found. However, in many boys an underlying etiology is contributory, and this should be identified and treated.

Treatment includes referral and optimal management of any associated brain neoplasms (e.g., optic nerve gliomas);[27][28] other hypothalamo-pituitary tumors; hamartomas; and neurodisability conditions such as hydrocephalus.

Patients who have developed CPP as a consequence of cranial radiation[29] should continue to be monitored for tumor recurrence and any other pituitary hormone deficiencies.

Very rarely, midline forebrain defects may be accompanied by CPP and other pituitary hormone abnormalities.[34] These patients should be monitored for evolving hormone deficiencies.

Sexual abuse has been reported as a precipitating cause of CPP.[37] Early pubertal development can regress with a change in environment.

Plus – gonadotropin-releasing hormone (GnRH) agonist

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ACUTE
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central precocious puberty (CPP)
Plus – 

gonadotropin-releasing hormone (GnRH) agonist

Treatment recommended for ALL patients in selected patient group

Continuous exposure to GnRH suppresses puberty, as it is only pulsatile exposure that triggers pubertal progression. GnRH agonists are the only effective treatment modality for CPP.

Recommended GnRH agonists include leuprolide, triptorelin, or goserelin depot preparations.[58]​ An implantable GnRH agonist, histrelin, has recently been used successfully. The implant is effective for at least one year, possibly more.[60][61]​ One study found that a single implant is effective for 2 years, so this option may be considered; however, use of a single implant for more than 12 months is not licensed.[59]

Treatment improves the adult height to a degree with rapidly progressing puberty, particularly in children <6 years old,[62][63][64][65]​ but is less convincing in girls >6 years old.[78] There is only minimally convincing evidence of an improvement in adult height with GnRH agonist treatment after the bone age of 12.5 years in girls and 14 years in boys.[66]​ Therefore, for children with more advanced bone age at presentation, parents need to be told that treatment may have little effect on adult height, and an informed discussion of costs and benefits is needed prior to recommending therapy.[67] There are few results of adult height benefit in boys. 

The suppression of puberty with these agents is reversible with few adverse effects. Initial treatment may result in uterine bleeding in girls and menopausal symptoms such as mood swings and hot flashes due to withdrawal of sex steroids. Bone mineral density and future reproductive function do not appear to be affected.[66]

Treatment should be stopped once an acceptable age of puberty is reached and should be individualized taking into account the chronologic age, bone age, growth velocity, and desires of the patient and family. Gonadotropin secretion recommences approximately 3 to 4 months after stopping treatment, with normal pubertal progress and fertility.

Primary options

leuprolide: children <25 kg body weight: 7.5 mg intramuscularly every 4 weeks, adjust dose according to response; children 25 to 37.5 kg body weight: 11.25 mg intramuscularly every 4 weeks, adjust dose according to response; children >37.5 kg body weight: 15 mg intramuscularly every 4 weeks, adjust dose according to response; children 2-11 years of age: 11.25 mg or 30 mg intramuscularly every 12 weeks

OR

triptorelin: children ≥2 years of age: 22.5 mg intramuscularly every 24 weeks

OR

histrelin: children ≥2 years of age: 50 mg (one implant) inserted subcutaneously in the upper arm every 12-24 months

OR

goserelin: consult specialist for guidance on dose

Consider – growth hormone (GH)

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ACUTE
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central precocious puberty (CPP)
Consider – 

growth hormone (GH)

Treatment recommended for SOME patients in selected patient group

Treatment with gonadotropin-releasing hormone (GnRH) agonists can lead to a reduction in the growth rate due to a reduction in GH and insulin-like growth factor 1 (IGF1) concentrations.

Addition of GH treatment to GnRH agonist therapy may be considered if the patient’s final height is likely to be significantly impaired. However, data on an improved adult height are not convincing.

The recommended dose is the same as for GH deficiency.[79][80]

Primary options

somatropin (recombinant): dose depends on brand used; consult specialist for guidance on dose

gonadotropin-independent precocious puberty (GIPP)

1st line – ketoconazole or aromatase inhibitor

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ACUTE
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gonadotropin-independent precocious puberty (GIPP)
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McCune-Albright syndrome or testotoxicosis
1st line – 

ketoconazole or aromatase inhibitor

Patients need pharmacotherapy to prevent the synthesis or action of gonadal steroids. Pharmacotherapeutic options include ketoconazole or an aromatase inhibitor (e.g., anastrozole, letrozole).[68][81]

Ketoconazole acts as an inhibitor of steroid synthesis and suppresses both gonadal and adrenal steroid production. It helps decrease testosterone levels and achieve good growth. Ketoconazole may cause severe liver injury and adrenal insufficiency. Its use requires expert guidance and it is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[75]

Aromatase inhibitors reduce growth rate and bone age advance. If used, antiandrogen agents may be required to reduce testosterone effects on pubic hair and genital development (see below).[71]​​

Primary options

ketoconazole: consult specialist for guidance on dose

OR

anastrozole: consult specialist for guidance on dose

or

letrozole: consult specialist for guidance on dose

Plus – supportive care for McCune-Albright syndrome

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ACUTE
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gonadotropin-independent precocious puberty (GIPP)
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McCune-Albright syndrome or testotoxicosis
Plus – 

supportive care for McCune-Albright syndrome

Treatment recommended for ALL patients in selected patient group

Hyperfunctioning of other endocrine glands observed with McCune-Albright syndrome (MAS), such as hyperthyroidism and Cushing disease, needs appropriate management.

Medroxyprogesterone may be used to stop vaginal bleeding in females with MAS, but it does not halt the progression of bone age or bony lesions.[76] Tamoxifen, an antiestrogen, has also been used in reducing vaginal bleeding.[77]

Laparoscopic cystectomy of ovarian cysts may be required in severe disease.

Consider – antiandrogen

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ACUTE
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gonadotropin-independent precocious puberty (GIPP)
|
McCune-Albright syndrome or testotoxicosis
Consider – 

antiandrogen

Treatment recommended for SOME patients in selected patient group

If aromatase inhibitors are used, antiandrogen agents may be required to reduce testosterone effects on pubic hair and genital development.[71]

Primary options

spironolactone: consult specialist for guidance on dose

OR

bicalutamide: consult specialist for guidance on dose

Consider – gonadotropin-releasing hormone (GnRH) agonist

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ACUTE
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gonadotropin-independent precocious puberty (GIPP)
|
McCune-Albright syndrome or testotoxicosis
Consider – 

gonadotropin-releasing hormone (GnRH) agonist

Treatment recommended for SOME patients in selected patient group

Prolonged sex-steroid exposure in McCune-Albright syndrome or testotoxicosis may have a direct maturational effect on the hypothalamus and can accelerate the onset of centrally mediated puberty, thus leading to secondary CPP. If this occurs, GnRH agonist therapy is indicated.

Recommended GnRH agonists include leuprolide, triptorelin, or goserelin depot preparations.[58]​ An implantable GnRH agonist, histrelin, has recently been used successfully. The implant is effective for at least 1 year, possibly more.[60][61] One study found that a single implant is effective for 2 years, so this option may be considered; however, use of a single implant for more than 12 months is not licensed.[59]

Primary options

leuprolide: children <25 kg body weight: 7.5 mg intramuscularly every 4 weeks, adjust dose according to response; children 25 to 37.5 kg body weight: 11.25 mg intramuscularly every 4 weeks, adjust dose according to response; children >37.5 kg body weight: 15 mg intramuscularly every 4 weeks, adjust dose according to response; children 2-11 years of age: 11.25 mg or 30 mg intramuscularly every 12 weeks

OR

triptorelin: children ≥2 years of age: 22.5 mg intramuscularly every 24 weeks

OR

histrelin: children ≥2 years of age: 50 mg (one implant) inserted subcutaneously in the upper arm every 12-24 months

OR

goserelin: consult specialist for guidance on dose

1st line – adjustment of ongoing hydrocortisone treatment

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ACUTE
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gonadotropin-independent precocious puberty (GIPP)
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congenital adrenal hyperplasia (CAH)
1st line – 

adjustment of ongoing hydrocortisone treatment

Optimum management with hydrocortisone (with or without fludrocortisone) therapy will help prevent rapid virilization in patients with GIPP due to CAH.

Primary options

hydrocortisone: 10-15 mg/square meter of body surface area/day orally given in 2-3 divided doses

OR

prednisone: 4-5 mg/square meter of body surface area/day orally

OR

dexamethasone: 0.03 to 0.3 mg/kg/day orally given in 2 divided doses

Consider – gonadotropin-releasing hormone (GnRH) agonist

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ACUTE
|
gonadotropin-independent precocious puberty (GIPP)
|
congenital adrenal hyperplasia (CAH)
Consider – 

gonadotropin-releasing hormone (GnRH) agonist

Treatment recommended for SOME patients in selected patient group

Prolonged sex-steroid exposure in CAH may have a direct maturational effect on the hypothalamus and can accelerate the onset of centrally mediated puberty, thus leading to secondary CPP. If this occurs, GnRH agonist therapy is indicated.

Recommended GnRH agonists include leuprolide, triptorelin, or goserelin depot preparations.[58]​ An implantable GnRH agonist, histrelin, has been recently used successfully. The implant is effective for at least 1 year, possibly more.[60][61] One study found that a single implant is effective for 2 years, so this option may be considered; however, use of a single implant for more than 12 months is not licensed.[59]

Primary options

leuprolide: children <25 kg body weight: 7.5 mg intramuscularly every 4 weeks, adjust dose according to response; children 25 to 37.5 kg body weight: 11.25 mg intramuscularly every 4 weeks, adjust dose according to response; children >37.5 kg body weight: 15 mg intramuscularly every 4 weeks, adjust dose according to response; children 2-11 years of age: 11.25 mg or 30 mg intramuscularly every 12 weeks

OR

triptorelin: children ≥2 years of age: 22.5 mg intramuscularly every 24 weeks

OR

histrelin: children ≥2 years of age: 50 mg (one implant) inserted subcutaneously in the upper arm every 12-24 months

OR

goserelin: consult specialist for guidance on dose

1st line – specialist referral and treatment

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ACUTE
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gonadotropin-independent precocious puberty (GIPP)
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tumors
1st line – 

specialist referral and treatment

Tumors of the ovary, testes, or adrenals need surgery. These may include ovarian tumors such as granulosa cell tumors, Leydig cell tumors, and gonadoblastoma; testicular Leydig cell tumor; or an adrenal virilizing tumor.

Human chorionic gonadotropin tumors are more difficult to treat and patients may need a combination of surgery, chemotherapy, and radiation. These germ cell tumors are a rare cause and may occur in the gonads, brain (usually in the pineal region), liver, retroperitoneum, and posterior mediastinum.[38]

1st line – identification and discontinuation of exogenous agent

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ACUTE
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gonadotropin-independent precocious puberty (GIPP)
|
exogenous estrogens or androgens
1st line – 

identification and discontinuation of exogenous agent

Exposure to exogenous hormones such as the oral contraceptive pill or testosterone gels may be responsible for early pubertal development in some patients. Estrogenic agents in cosmetics and food products have also been implicated in resulting in an earlier age of puberty; "epidemics" of premature thelarche (isolated breast development) in some geographic areas may be linked to an environmental exposure to estrogens.[22] Identification and discontinuation of these agents will halt the progress of puberty.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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